Enol-thioethers of ketosteroids and method of preparing the same



?atentec Get. 12, 1943 UNITED STATES PATENT OFFICE ENOL-THIOETHERS OF KETOSTEROIDS AND METHOD OF PREPARING THE SAME Louis Dorfman, New York, and Seymour Bernstein, Pearl River, N. Y., assignors, by mesne assignments, to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application March 26, 1945, Serial No. 585,010

3 Claims.

formation of a new class of organic compounds 10 which may be designated as enol-thioethers of 3- keto-A -cyclopentanopolyhydrophenanthrenes.

The following equation showing the reaction of M-cholestenone-S with ethyl mercaptan is a specific example of the type reaction:

CH CH1 CH3 CH3 l CH-CHz-CHrCHrC CHa C D 2C2H5BH 11 position or in the 12 position a member of the 40 group consisting of keto, hydroxy and alkoxy radicals. It may also have in the 17 position a radical such as hydroxy, ethoxy, hydroxyethyl, acetoxyethyl, or the normal bile acid side chain,

--41 11-0 Hz-O H2-C 0 OH nor-bile acid side chain,

blsnor-bile acid side chain,

CH3 -4H-000H A -an- 30 2 or the etio side chain, -COOH either as the free acid or in the form of the corresponding esters. The new compounds of the present invention may be illustrated by the following general for- 5 mula:

wherein R is alkyl or alkaryl and A and B designate rings A and B of a cyclopentanopolyhydrophenanthrene compound.

While we believe that the above general formula represents the compounds formed in carrying out our invention we do not wish to be limited to A cyclopentanopolyhydrophenanthrene structure as the compounds may have the A- cyclopentanopolyhydrophenanthrene structure.

The compounds of the present invention are generally white solids, although in some instances they may be viscous oils of similar color. They are practically insoluble in water but are soluble in ether, chloroform, carbon tetrachloride, etc. As a general rule they have low melting points and give a positive Rosenheim color test for conjugated double bond systems.

Mercaptans are well known compounds, usually available as alkyl mercaptans such as methyl mercaptan, ethyl mercaptan, propyl mercaptan, butyl mercaptan, isobutyl mercaptan, etc. We can also use alkaryl mercaptans such as benzyl mercaptan, phenylethyl mercaptan, phenylpropyl mercaptan, phenylbutyl mercaptan, phenylisobutyl mercaptan, phenyl-2-ethylhexyl mercaptan, and the like.

We prefer to carry out the reaction between a 3-keto A -cyclopentanopolyhydrophenanthrene and a mercaptan at room temperature in the presence of dehydrating agents such as fused zinc chloride and anhydrous sodium sulfate or dry I-ICl. some extent exothermic in character, causing the mixture to Warm up slightly. A convenient meth- 55 0d of conducting the reaction is to mix the re- In fact, the reaction generally is to actants with a dehydrating agent and allow the mixture to stand at a temperature of from about 1 C. to about 35 C. for from about one-half hour to about 24 hours or longer.

In recovering the product from the reaction mixture, the excess of mercaptan is first removed,

preferably by evaporation invacuo. The mixture is then diluted with water and degassed in vacuu, to remove traces of mercaptan. The. desired prod-- not is taken up in a water immiscible solvent such as ether, carbon tetrachloride, chloroform, etc., and washed with water to remove water-soluble impurities.

Upon removal of the solvent the product is obtained as a viscous oil which usually solidifies on standing. The product can be further purified by recrystallization from acetone, acetone-ether mixture, or similar organic solvents.

The compounds of the present invention are useful as pharmaceuticals and in the preparation of therapeutically useful steroids.

Our invention will now be illustrated in greater detail by means of the followin specific examples. It will be understood, of course, that these examples are given for purposes of illustration and are not to be considered as limiting our invention to the particular details described therein.

Example 1 purple coloration disappeared. The white. oil so' obtained was taken up in ether, and the extract was washed with water until neutral to litmus. The ether solution was dried with anhydrous sodium. sulfate and was evaporated, to give 1.174 g. of a slightly yellow viscous oil. This oil on standing, crystallized to give a yellow solid which was recrystallized from acetone to give 570 mg. of the desired product in crude form. On recrystalliza-i tion from ether-acetone and acetone, there was obtained 435 mg. of pure product havinga melting point of 98-99.5 C. The product, enol- 4 ethylthioether of A -cho1estenone-3, gave a positive Rosenheim color test for conjugated double bond system. On analysis for carbon, hydrogen and sulfur, the results were in close agreement with the theoretical.

Example 2 7 One cc. of ethyl mercaptan was added to a mixture of 0.1 g. of testosterone propionate, 0.05 g. of freshly fused Zinc chloride and 0.1 g. of anhydrous sodium sulfate. The resulting red solution was allowed to stand at room temperature for 18 hours. The excess ethyl mercaptan was evaporated in vacuo. Water was added and the mixture was degassed in vacuo. During this treatment the deep red coloration disappeared, and an oily solid was obtained. The product was taken up in ether and was washed with water until neutral. The ether extract was dried with anhydrous sodium sulfate and on evaporation the desired product was obtained as a yellow viscous oil. The product, enol-ethylthioether of testosteronepropionate, gave a positive Rosenheim test for conjugated double bond systems.

We claim:

1. The method of producing the enol lower alkyl thioethers of testosterone-l'l propionate which comprises reacting testosterone-lT-propionate with a lower alkyl mercaptan in the presence of a dehydrating agent.

2. The method of producing the enol-ethylthioether of testosterone-l'l-propionate which comprises mixing testosterone-17 -propionate with ethyl mercaptan in the presence of a dehydrating agent. i

3. The enol-ethyl-thioether of testosterone-17- propionate.

LOUIS DORFMAN. SEYMOUR BERN STEIN.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,344,997 Miescher Mar. 28, 1944 2,363,338 Koster Nov. 21,. 1 944.-

OTHER REFERENCES Schwenk, Journal American Chem. $00., 60, pages 1702 to 1703 (1938). 

